In the United States, 27,000 women are newly diagnosed and approximately 14, 000 women die from ovarian cancer (OvCa) annually [1]. Such high mortality rates are due to majority of patients (75%) presenting with advanced (stage III or greater) disease at the time of diagnosis [2]. More than 90% of the patients have better prognosis if the cancer is detected in its earliest stages. Treatment of epithelial ovarian cancer generally involves surgical debulking followed by chemotherapy with a combination of platinum and a taxane-containing agent. However, majority of patients recur and ultimately succumb to their cancer. Consequently, there is a vast need to develop new therapeutics that can be more effective in treating ovarian cancer and delaying or preventing recurrences. Novel therapies that target ovarian tumorigenesis are extensively been researched, but we have yet to come up with a promising drug.
Nanotechnology based tools and techniques are rapidly emerging in the fields of medical imaging and targeted drug delivery. Cerium oxide is a rare-earth oxide that is found in the lanthanide series of the periodic table. Nanocrystalline cerium oxide (nanoceria) exhibits a blue shift in the ultraviolet absorption spectrum, the shifting and broadening of Raman allowed modes and lattice expansion as compared to bulk cerium oxide indicating its unique properties. Nanoparticulate cerium oxide, also known as nanoceria or NCe, has emerged as a fascinating and lucrative material in biomedical science due to its unique ability to switch oxidation states between (III) and (IV) depending upon the environment. The ability to switch between mixed oxidation states of nanoceria is comparable to biological antioxidants. This imparts nanoceria with a very important biological property of radical scavenging which can be tuned based upon the retention of oxygen vacancies (defects) and concentration of Ce3+ species in nanoceria. The reversibility of oxidation state is the key property in making nanoceria a potent antioxidant, thereby eliminating the need for repeated dosage. Previous studies have demonstrated that cerium oxide nanoparticles possess excellent antioxidant properties and act as potent, regenerative free radical scavengers in biological systems [3,4,5]. These regenerative antioxidant properties are due, in part, to the valence structure of the cerium atom combined with inherent defects in the crystal lattice structure, which are magnified at the nano scale. It has been suggested that the unique structure of engineered cerium oxide nanoparticles, with respect to valence and oxygen defects, promotes cell longevity and decreases toxic insults by virtue of its antioxidant effects that occur when the nanoparticles enter the cells [6] preventing the accumulation of reactive oxygen species (ROS) in cell [3].
Tumor angiogenesis is characterized by the formation of new, irregular blood vessels from a preexisting vascular network. This abnormal angiogenesis is required for the growth, survival, and metastasis of most solid tumors [7,8]. Vascular endothelial growth factor (VEGF) is one of the most important proangiogenic factors, which acts as a mitogen for vascular endothelial cells in vitro and as an angiogenic factor in vivo [9]. It is over expressed in various human cancers [10, 11, 12, 13] including ovarian cancer. Recently it has been suggested that ROS played an important role in regulating tumor induced angiogenesis by controlling VEGF production. Enhanced production of VEGF has been shown to correlate with a poor outcome for patients with both early and advanced OvCa. Various anti-angiogenic agents have been and are undergoing evaluations in ovarian cancer clinical trials. A phase II study of single-agent bevacizumab (a monoclonal antibody directed against VEGF) showed promising results [14]. Therefore, VEGF signaling is becoming the focus of antiangiogenesis-targeted therapies in ovarian cancer.
The present disclosure concerns the novel approach of using cerium oxide nanoparticles as a therapeutic agent for ovarian cancer treatment. Our data demonstrate that NCe was able to curtail ovarian cancer growth, migration and invasion and its main mechanism of action appears to be via inhibition of angiogenesis by targeting the endothelial cells